Production process of aminomethyl group-containing benzamide compound

ABSTRACT

There is provided a process for producing an aminomethyl group-containing benzamide compound represented by the general formula (II): wherein —CONH2 and —X represent a substituent on the benzene ring and —CONH2 exists at the meta- or para-position of —CH2NH2, and X and n are as defined below, which comprises hydrating an aminomethyl group-containing benzonitrile compound represented by the general formula (I): wherein —CN and —X represent a substituent on the benzene ring and —CN exists at the meta- or para-position of —CH2NH2, X represents a chlorine atom or a fluorine atom, and n represents an integer of 0 to 4, provided that, when n is 2 or more, X may be the same or different.

CROSS-REFERENCE TO RELATED APPLICATIONS

The application is an application filed under 35 U.S.C. § 111 (a)claiming pursuant to 35 U.S.C. § 119 (e) of the filing date ofProvisional Application 60/383,111 on May 28, 2002, pursuant to 35U.S.C. § 111 (b).

FIELD OF THE INVENTION

The present invention relates to a production process of an aminomethylgroup-containing benzamide compound. The aminomethyl group-containingbenzamide compound is useful as intermediates for medicaments,pesticides, liquid crystals and functional polymeric monomer.

BACKGROUND OF THE INVENTION

As the production process of an aminomethyl group-containing benzamidecompound, several processes are known. Examples of the productionprocess of 4-aminomethylbenzamide include a process of suspending4-cyanobenzamide in ammonia-containing methanol and reacting thesuspension at room temperature using Rh/Al₂O₃ as a catalyst (UnexaminedJapanese Patent Publication (Kokai) No. 60-139670), a process forcontact hydrogenation of 4-cyanobenzamide in the presence of ammoniausing a sponge nickel catalyst (Unexamined Japanese Patent Publication(Kohyo) No. 8-505862) and a process of treating a hydrochloride of4-aminomethylbenzoate ester with ammonia (U.S. Pat. No. 3,817,981).

The process using 4-cyanobenzamide as a starting material exhibits poorproductivity and low yield because 35 the reaction is conducted at lowconcentration. Also the process using 4-aminomethylbenzoate ester as astarting material does not exhibit good productivity because it requiresa multi-stage reaction and a complicated operation in order to obtainthe starting material.

An object of the present invention is to produce an aminomethylgroup-containing benzamide compound with high purity, which is useful asintermediates for medicaments and pesticides, represented by the generalformula (II):

wherein —CONH₂ and —X represent a substituent on the benzene ring andexist at the meta- or para-position of —CONH₂—CH₂NH₂, X represents achlorine atom or a fluorine atom, and n represents an integer of 0 to 4,provided that, when n is 2 or more, X may be the same or different, withhigh yield using an industrially useful process.

The present inventors have found that the above object can be achievedby converting a cyano group (—CN) on the benzene ring into an amidegroup (—CONH₂) using, as a starting material, an aminomethylgroup-containing benzonitrile compound represented by the generalformula (I):

wherein —CN and —X represent a substituent on the benzene ring and —CNexists at the meta- or para-position of —CH₂NH₂, X represents a chlorineatom or a fluorine atom, and n represents an integer of 0 to 4, providedthat, when n is 2 or more, X may be the same or different, and thus thepresent invention has been completed.

SUMMARY OF THE INVENTION

That is, the present invention is directed to the followings:

-   -   [1] A process for producing an aminomethyl group-containing        benzamide compound represented by the general formula (II):        wherein —CONH₂ and —X represent a substituent on the benzene        ring and —CONH₂ exists at the meta- or para-position of —CH₂NH₂,        and X and n are as defined below, which comprises hydrating an        aminomethyl group-containing benzonitrile compound represented        by the general formula (I):        wherein —CN and —X represent a substituent on the benzene ring        and —CN exists at the meta- or para-position of —CH₂NH₂, X        represents a chlorine atom or a fluorine atom, and n represents        an integer of 0 to 4, provided that, when n is 2 or more, X may        be the same or different.    -   [2] The process according to [1], wherein the hydration is        conducted in the presence of a concentrated sulfuric acid.    -   [3] The process according to [1], wherein the hydration is        conducted in an alcohol solvent in the presence of a basic        compound.    -   [4] The process according to [1], wherein the hydration is        conducted in the presence of hydrogen peroxide.    -   [5] The process according to [4], wherein the hydration is        conducted in the presence of a basic compound.    -   [6] The process according to [1], wherein the hydration is        conducted using a sponge copper as a catalyst.    -   [7] The process according to [1], wherein the aminomethyl        group-containing benzonitrile compound of the general        formula (I) is m- or p-aminomethylbenzonitrile and the        aminomethyl group-containing benzamide compound of the general        formula (II) is m- or p-aminomethylbenzamide.    -   [8] The process for producing an aminomethyl group-containing        benzamide compound according to any one of [1] to [7], which        uses an aminomethyl group-containing benzonitrile compound        represented by the general formula (I):        wherein —CN and —X represent a substituent on the benzene ring        and —CN exists at the meta- or para-position of —CH₂NH₂, and X        and n are as defined below, which is obtained by selectively        reducing either of nitrile groups of a phthalonitrile compound        represented by the general formula (III):        wherein —CN and —X represent a substituent on the benzene ring,        two —CN (s) exist at the meta- or para-position, X represents a        chlorine atom or a fluorine atom, and n represents an integer of        0 to 4, provided that, when n is 2 or more, X may be the same or        different.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will now be described in detail.

The aminomethyl group-containing benzonitrile compound represented bythe general formula (I):

wherein —CN and —X represent a substituent on the benzene ring and —CNexists at the meta- or para-position of —CH₂NH₂, X represents a chlorineatom or a fluorine atom, and n represents an integer of 0 to 4, providedthat, when n is 2 or more, X may be the same or different, used in thepresent invention can be produced easily in a large amount by thehydrogenation reaction of a one-side nitrile group of a correspondingdinitrile compound represented by the general formula (III):

wherein —CN and —X represent a substituent on the benzene ring and two—CN (s) exist at the meta- or para-position, X represents a chlorineatom or a fluorine atom, and n represents an integer of 0 to 4, providedthat, n is 2 or more, X may be the same or different. For example,p-aminomethylbenzonitrile and m-aminomethylbenzonitrile can berespectively obtained in a reaction yield of 80% by selectivelyhydrogenating a one-side nitrile moiety of terephthalonitrile andisophthalonitrile using a sponge nickel/cobalt catalyst pretreated withhydrogen (Japanese Unexamined Patent Publication (Kokai) No. 10-204048).4-aminomethyl-2,3,5,6-tetrafluorobenzonitrile and3-aminomethyl-2,4,5,6-tetrafluorobenzonitrile can be respectivelyproduced by selectively hydrogenating a one-side nitrile moiety oftetrafluoroterephthalonitrile and tetrafluoroisophthalonitrile, whichare obtained by fluorinating tetrachloroterephthalonitrile andtetrachloroisophthalonitrile obtained by chlorinating terephthalonitrileand isophthalonitrile. When tetrafluoroterephthalonitrile is reactedunder the same conditions as in case of p-aminomethylbenzonitrile,4-aminomethyl-2,3,5,6-tetrafluorobenzonitrile can be obtained athigh-performance liquid chromatography area percentage of 38% (analysisconditions are the same as described in EXAMPLES).

Examples of the process of hydrating the aminomethyl group-containingbenzonitrile compound represented by the general formula (I):

wherein —CN and —X represent a substituent on the benzene ring and —CNexits at the meta- or para-position of —CH₂NH₂, X represents a chlorineatom or a fluorine atom, and n represents an integer of 0 to 4, providedthat, when n is 2 or more, X may be the same or different, used in thepresent invention includes:

-   -   (1) a process of hydrating a nitrile group in the presence of        sulfuric acid;    -   (2) a process of hydrating a nitrile group in an organic solvent        in the presence of a basic compound;    -   (3) a process of hydrating a nitrile group in the presence of        hydrogen peroxide; and    -   (4) a process of hydrating a nitrile group in the presence of a        sponge Cu.

The above processes (1) to (4) will now be described.

(1) Process of Hydrating a Nitrile Group in the Presence of SulfuricAcid

Sulfuric acid used in this process is preferably concentrated sulfuricacid, but may contain water described below, which is allowed tocoexist. The amount of sulfuric acid is an amount enough to dissolve thebenzonitrile compound as the raw material. When the amount is too small,a reaction product is deposited and it becomes difficult to handle. Onthe other hand, when using it in an excess amount, it is not preferredin view of the environment because the amount of wastes increases.Although optimum amount varies depending on the solubility of theaminomethyl group-containing benzonitrile as the raw material, theamount is preferably from 1 to 20 times, and more preferably from 2 to10 times, by weight larger than that of the aminomethyl group-containingbenzonitrile compound as the raw material.

When the reaction temperature is low, the reaction proceeds slowly. Onthe other hand, when the reaction temperature is high, the aminomethylgroup-containing benzamide compound as the product is hydrolyzed and theyield is lowered. Therefore, the reaction temperature is preferably from0 to 80° C., and more preferably from 5 to 60° C.

During the reaction, water is allowed to coexist in an amount requiredfor hydration reaction. The amount of water, which is allowed tocoexist, is preferably from 1 to 50 mol, and more preferably from 1.1 to20 mol, per mol of the aminomethyl group-containing benzonitrilecompound as the raw material. An amino group-containing benzonitrilecompound which may contain water can also be used.

Since the aminomethyl group-containing benzamide compound thus producedexists in the form of an acidic salt, it is isolated and purified byneutralizing the acidic salt, concentrating water and collecting thedeposited crystal with filtration. In case an inorganic salt iscontained in the crystal collected by filtration, it can be isolated andpurified by repeating an operation of recrystallization from water anddrying the crystal collected by filtration.

(2) Process of Hydrating a Nitrile Group in a Solvent in the Presence ofa Basic Compound

In case of the process (2), the basic compound to be used is preferablya hydroxide of an alkali metal or an alkali earth metal, such as sodiumhydroxide, potassium hydroxide or calcium hydroxide. The amount ispreferably to from 0.01 to 5 times, and more preferably 0.02 to 2 times,by weight larger than that of the aminomethyl group-containingbenzonitrile to be used.

As the organic solvent, any solvent can be used as far as it does notexert an adverse influence on the reaction and an alcohol-type solventis suitable in view of the solubility of the raw material and the basiccompound. Specific examples of the alcohol solvent include alkyl alcoholsuch as methanol, ethanol, isopropanol, or tert-butanol; alicyclicalcohol such as cyclohexyl alcohol; and aromatic alcohol such as benzylalcohol.

During the reaction, water is allowed to coexist in an amount requiredfor hydration reaction. The amount of water, which is allowed tocoexist, is preferably from 1 to 20 mol, and more preferably from 1.1 to10 mol, per mol of the aminomethyl group-containing benzonitrilecompound as the raw material. An amino group-containing benzonitrilecompound which may contain water can also be used.

The reaction temperature varies depending on the kind of the solvent tobe used, but is preferably from 20° C. to the boiling point of thesolvent, and more preferably from 40° C. to the boiling point of thesolvent.

The aminomethyl group-containing benzamide compound thus produced can beisolated and purified by neutralizing a basic compound used, distillingoff the solvent at low temperature under reduced pressure,recrystallizing from water and drying the crystal collected byfiltration.

(3) Process of Hydrating a Nitrile Group in the Presence of a HydrogenPeroxide

This reaction is a reaction which is reported by Radziszewski [Rer., 18,355 (1885)] and known for long, however, it is unexpected to employhydrogen peroxide as an oxidizing agent in a compound having an aminogroup, such as the compound of the present invention.

Although hydrogen peroxide is used in an amount of 2 mol per mol of abenzonitrile compound as a raw material, theoretically, the amountneeded varies depending on the reaction conditions. The amount ofhydrogen peroxide used in the present invention is preferably from 1.5to 3.5 mol, and more preferably from 1.6 to 2.5 mol, per mol of the rawmaterial so that the reaction is completed and the residual amount ofhydrogen peroxide is reduced.

When the reaction temperature is low, the reaction proceeds slowly. Onthe other hand, when the reaction temperature is high, the aminomethylgroup-containing benzamide compound as the product is likely to behydrolyzed and also the reaction between an aminomethyl group andhydrogen peroxide is accelerated and the yield is lowered. Therefore,the reaction temperature is preferably from 0 to 60° C., and morepreferably from 1 to 40° C.

In case of the process (3), a basic compound is preferably used as acatalyst. The basic compound is preferably a hydroxide of an alkalimetal or an alkali earth metal, such as sodium hydroxide, potassiumhydroxide or calcium hydroxide. The amount may be any amount as far assufficient reaction rate can be obtained, but is preferably to from 0.01to 1.5 times, and more preferably 0.05 to 1.0 times, by weight largerthan that of the aminomethyl group-containing benzonitrile to be used.

As the reaction solvent, water is used and may be supplied in the formof hydrogen peroxide water. Also the reaction solvent may contain theother solvent as far as it does not exert an adverse influence on thereaction as well as isolation and purification. A hydrate of anaminomethyl group-containing benzonitrile compound can also be used.

The amount of water is preferably from 1 to 20 times, and morepreferably from 2 to 10 times, by weight larger than that of theaminomethyl group-containing benzonitrile compound to be used.

With respect to isolation and purification of the aaminomethylgroup-containing benzamide compound thus produced, the crystal isdeposited or dissolved according to the concentration. In case thecrystal is deposited, the crystal is collected by filtration and, ifnecessary, an operation of recrystallization from water is conducted. Incase the crystal is dissolved, the compound can be isolated and purifiedby concentrating water, collecting the deposited crystal by filtration,optionally repeating an operation of recrystallization from water anddrying the crystal collected by filtration.

(4) Process of Hydrating a Nitrile Group in the Presence of a Sponge Cu

The amount of a sponge copper catalyst used herein may be any amount asfar as sufficient reaction rate can be obtained, but is preferably from0.01 to 5 times, and more preferably 0.05 to 3 times, by weight largerthan that of the aminomethyl group-containing benzonitrile compound asthe raw material. The solvent to be used is preferably water, or acombination of an alcohol-type solvent and water required for hydrationreaction. In this case, the reaction proceeds without adding an acid ora basic compound.

The amount of the solvent to be used is preferably from 2 to 100 times,and more preferably 3 to 20 times, by weight larger than that of theaminomethyl group-containing benzonitrile compound as the raw material.The reaction temperature is preferably from 5 to 160° C., and morepreferably from 30 to 120° C. With respect to the reaction pressure, thereaction can be conducted at normal pressure or under pressure.

With respect to isolation and purification of the aaminomethylgroup-containing benzamide compound thus produced, the crystal isdeposited or dissolved according to the concentration. In case thecrystal is deposited, the crystal is collected by filtration and, ifnecessary, an operation of recrystallization from water is conducted. Incase the crystal is dissolved, the compound can be isolated and purifiedby concentrating water, collecting the deposited crystal by filtration,optionally repeating an operation of recrystallization from water anddrying the crystal collected by filtration.

The operation of recrystallization or crystallization from water in therespective processes (1) to (4) is conducted by the following reasons.That is, it is effective to remove impurities such as aminomethylgroup-containing benzoic acid produced as a result of hydrolysis of anamide group of the aminomethyl group-containing benzamide compoundduring the isolation operation.

In the present invention, raw materials such as aminomethylgroup-containing benzonitrile, solvent, catalyst and reaction base (forexample, alkali or hydrogen peroxide) may be added and mixed in anymanner.

EXAMPLES

The following Examples illustrate the present invention in detail, butare not intended to limit the present invention.

In the analysis of products, high-performance liquid chromatography wasused. The conditions are shown below.

<Conditions of High-Performance Liquid Chromatography>

-   Column: Shodex® (manufactured by SHOWA DENKO K.K.) C18M-4E+precolumn-   Column temperature: column oven: 40° C.-   Eluent: water/acetonitrile/acetic acid=2500/500/15 (ml)+sodium    1-octanesulfonate: 6.45 g-   Eluent flow rate: 1 ml/min-   Detector: UV (230 nm)

Example 1

In a reactor equipped with a motor-driven stirrer, 3450 g ofconcentrated sulfuric acid (reagent, purity: 98%) was charged and 1148 gof a hydrate of p-aminomethylbenzonitrile (958.6 g/7.253 mol asp-aminomethylbenzonitrile, purity: 83.5%, moisture: 189.4 g/10.522 mol)was gradually added so that the reaction temperature reaches 40 to 50°C., followed by mixing with stirring at 50° C. for 3 hours. After thecompletion of the reaction, 1440 g of water was added and the solutionwas stirred at 40° C. for one hour, then at room temperature overnight.The deposited crystal was collected by filtration and suspended in 4000g of water and then neutralized by slowly adding 2117 g of potassiumhydroxide (reagent, purity: 85%) while maintaining the temperature at 40to 50° C.

The deposited p-aminomethylbenzamide-containing potassium sulfatecrystal was collected by filtration and then cooled to 5° C. Thedeposited crystal was collected by filtration and then dried to obtain521.6 g of p-aminomethylbenzamide.

An operation of recrystallization from the filteredp-aminomethylbenzamide-containing potassium sulfate crystal was repeatedfive times to obtain 421.7 g of p-aminomethylbenzamide (total yieldbased on p-aminomethylbenzonitrile was 84%).

The purity of p-aminomethylbenzamide determined by analyzing usinghigh-performance liquid chromatograph was 97% or higher.

Example 2

In a reactor equipped with a motor-driven stirrer, 416 g oftert-butanol, 31.9 g of potassium hydroxide (reagent, purity: 85%) and59.5 g of a hydrate of p-aminomethylbenzonitrile (50.0 g/0.378 mol asp-aminomethylbenzonitrile, purity: 84%, moisture: 9.5 g/0.528 mol) werecharged in sequence and stirred at 80° C. for 2 hours. After thecompletion of the reaction, the reaction solution was cooled to roomtemperature and neutralized with 193.7 g of an aqueous 15 wt % sulfuricacid solution, and then the resulting potassium sulfate crystal wasremoved by filtration in a hot state at 70° C. Tert-butanol in theresulting filtrate was concentrated under reduced pressure, cooled to 5°C. and then stirred for 2 hours. The deposited crystal was collected byfiltration and then dried to obtain 46.6 g of p-aminomethylbenzamide(yield based on p-aminomethylbenzonitrile was 82%).

The purity of p-aminomethylbenzamide determined by analyzing usinghigh-performance liquid chromatograph was 99% or higher.

Example 3

In a reactor equipped with a motor-driven stirrer, 45 g of water, 1.38 gof sodium hydroxide (reagent, purity: 96%) and 43.56 g ofp-aminomethylbenzonitrile were charged in this sequence and then stirredat room temperature. 74.8 g of 30 wt % hydrogen peroxide water wasgradually added so that the reaction temperature reaches 30° C. orlower, followed by mixing with stirring. After foaming and temperaturerise were terminated, the reaction solution was cooled to 5° C. Thedeposited crystal was collected by filtration and then dried to obtain41.92 g of p-aminomethylbenzamide (yield based onp-aminomethylbenzonitrile: 81%). The purity of p-aminomethylbenzamidedetermined by analyzing using high-performance liquid chromatograph was97%.

Example 4

In a 100 ml autoclave (manufactured by Nitto Koatsu Co., Ltd., material:SUS-316), 43 g of water, 11.5 g of a water-containingp-aminomethylbenzonitrile (10 g as p-aminomethylbenzonitrile, purity:86.7%.) and 2.0 g of sponge copper (R-300C, manufactured by NIKKO RICACORPORATION) were charged and, after sealing the autoclave, theatmosphere in the autoclave was replaced by nitrogen and the reactionwas conducted at 100° C. for 6 hours. After the completion of thereaction, the catalyst was collected by filtration and the filtrate wascooled to 5° C., and then the crystal was collected by filtration. 10.0g of the resulting crystal (wet form, containing 8.05 g ofp-aminomethylbenzamide) was suspended in 43 g of water and dissolvedwith heating to 70° C., followed by cooled again to 5° C., filtrationand further drying to obtain 7.99 g of p-aminomethylbenzamide (yieldbased on p-aminomethylbenzonitrile: 71%). The purity ofp-aminomethylbenzamide determined by analyzing using high-performanceliquid chromatograph was 99% or higher.

Example 5

The same operation as in Example 3 was conducted, except thatm-aminomethylbenzonitrile was used in place ofp-aminomethylbenzonitrile. As a result, 38.11 g ofm-aminomethylbenzamide was obtained (yield based onm-aminomethylbenzonitrile: 77%). The purity of m-aminomethylbenzamidedetermined by analyzing using high-performance liquid chromatograph was97%.

INDUSTRIAL APPLICABILITY

According to the present invention, an aminomethyl group-containingbenzamide compound with high purity can be produced with high yield bythe hydration reaction of an aminomethyl group-containing benzonitrilecompound which is easily obtained from a phthalonitrile compound.

1. A process for producing an aminomethyl group-containing benzamidecompound represented by the general formula (II):

wherein —CONH₂ and —X represent a substituent on the benzene ring and—CONH₂ exists at the meta- or para-position of —CH₂NH₂, and X and n areas defined below, which comprises hydrating an aminomethylgroup-containing benzonitrile compound represented by the generalformula (I):

wherein —CN and —X represent a substituent on the benzene ring and —CNexists at the meta- or para-position of —CH₂NH₂, X represents a chlorineatom or a fluorine atom, and n represents an integer of 0 to 4, providedthat, when n is 2 or more, X may be the same or different.
 2. Theprocess according to claim 1, wherein the hydration is conducted in thepresence of a concentrated sulfuric acid.
 3. The process according toclaim 1, wherein the hydration is conducted in an alcohol solvent in thepresence of a basic compound.
 4. The process according to claim 1,wherein the hydration is conducted in the presence of hydrogen peroxide.5. The process according to claim 1, wherein the hydration is conductedin the presence of a basic compound.
 6. The process according to claim1, wherein the hydration is conducted using a sponge copper as acatalyst.
 7. The process according to claim 1, wherein the aminomethylgroup-containing benzonitrile compound of the general formula (I) is m-or p-aminomethylbenzonitrile and the aminomethyl group-containingbenzamide compound of the general formula (II) is m- orp-aminomethylbenzamide.
 8. The process according to any one of claims 1to 7, which uses an aminomethyl group-containing benzonitrile compoundrepresented by the general formula (I):

wherein —CN and —X represent a substituent on the benzene ring and —CNexists at the meta- or para-position of —CH₂NH₂, and X and n are asdefined below, which is obtained by selectively reducing either ofnitrile groups of a phthalonitrile compound represented by the generalformula (III):

wherein —CN and —X represent a substituent on the benzene ring, two—CN(s) exist at the meta- or para-position, X represents a chlorine atomor a fluorine atom, and n represents an integer of 0 to 4, providedthat, when n is 2 or more, X may be the same or different.